16beta-lower alkylthio-17beta-hydroxy-estren-3-one and production thereof



United States Patent 3,277,123 16,8-LOWER ALKYLTHIO-HB-HYDROXY-ESTREN-3-ONE AND PRODUCTION THEREOF Norio Tokutake, Hyogo Prefecture, Japan,assignor to Shionogi & Co., Ltd., Fukushima-ku, Osaka, Japan No Drawing.Filed Mar. 1, 1963, Ser. No. 262,211 Claims priority, applicagogidaapan,Mar. 10, 1962, 6 Claims. (Cl. 260-3974) The present invention relates to16,8-lower alkylthiol7}3-hydroxy-estren-3-one and production thereof.

The said 165-lower alkylthio-l7B-hydroxy-estren-3-one is represented bythe formula:

wherein R is a lower alkyl group (e.g. methyl, ethyl, propyl, butyl) anda double bond exists between 4- and 5- positions or between 5- and10-posi-tions. This compound (I) possesses a variety of physiologicalactivities such as uterotropic activity, pituitary gonadotrophininhibiting activity and deciduomatogenic activity. Accordingly, it isuseful as an artificial hormonic substance.

The lfifi-lower alkylthio-17fl-hydroxy-estren-3-one (I) is prepared bytreating 16 3-lower alkylthio-1,4-dihydro- 3,17/3-estradiol 3-loweralkyl ether with an acid (e.g. hydrochloric acid, sulfuric acid, nitricacid, acetic acid, oxalic acid).

The starting material, 16B-lower alkylthio-l,4-dihydro- 3,17B-estradiol3-lower alkyl ether, is represented by the formula:

MI I

Chem. Soc., vol. 79, p. 2005 (1959)], according to the following scheme:

Treatment with potassium lower alkylmercaptide in acetone.

Reduction with lithium aluminum hydride.

3,277,123 Patented Oct. 4, 1966 Reduction with lithium and lower alkanolin liquid ammonia.

MI I

wherein R and R each has the same significance as designated above.

The reaction readily proceeds by treating the starting compound (II)with an acid in a hydrous medium at a temperature from room temperature(15 to 30 C.) to reflux temperature. There is produced either 16B-loweralky1thio-17fl-hydroxy-5(10)-estren-3-one or 16B-loweralkylthio-l7B-hydroxy-4-estren-3-one depending on the reactionconditions such as the kind of the employed acid and the reactiontemperature, each of the said isomers being represented by the formula,respectively:

(DH SR wk Tsa to the A compound (Ib) by subjecting the former to thetreatment with an acid under the said stronger reaction conditions, theformer may be considered as an intermediate to the latter.

The thus produced 16B-lower alkylthio-l7B-hydroxyestren-3-one (I) maybe, if necessary, acylated on the 17/3-hydroxyl group according to a perse conventional procedure. For instance, the 16/3-loweralkylthio-17fihydroxy-estren-3-one (I) is treated with a lower alkanoicanhydride (e.g. acetic anhydride, propionic anhydride) and an organicbase (e.g. pyridine, picoline) at room temperature (15 to 30 C.) orwhile refluxing to give the 17 B-lower alkanoate.

The 16,8-lower alkylthio-l7fi-hydroxy-estern-3-one, i.e. lfi-loweralkylthio-l7 3-hydroxy-5(I0) -estren-3-one (Ia) and lofi-loweralkylthio-I7B-hydroxy-4-estrene3'-one (Ib),

and the acylate thereof possess a variety of physiological activities asstated above. For instance, 16/3-ethy1thio-171S-hydroxy-5(10)-estren-3-one produced marked inhibition ofgonadotrophin secretion at the dosage up to 10 mg. without showingandrogenic response, when administered orally or subcutaneously to mice.This compound also produced complete block of decidual growth induced bysubcutaneous administration of 3.6 mg. of progesterone, whenintra-uterine injection of the same, 0.2 mg. per horn, was carried outon mice. The same compound also enhanced the action of estradioladministered simultaneously and showed uterotropic activity by itself inthe test using mice. Further, for example, 16,8-ethy1-thio-17,13-hydroxy-4-estren-3-one produced significant inhibition ofgonadotrophin secretion at the dosage up to 10 mg. while showingandrogenic response, when orally or subcutaneously administered to mice.Although this compound did not inhibit the action of estradioladministered simultaneously, it produced uterotropic activity by itselfin the test using mice. Thus, these products are useful as artificialhormonic substances.

The following examples set forth the presently-preferred embodiments ofthe present invention. In these examples, the abbreviations are intendedto have conventional meanings: e.g., g., gram(s); mg, milligram(s); ml.,millilitre (s); C., degrees centigrade.

Example 1 To a solution of 16B-ethylthio-l,4-dihydro-3,17,8-estradiol3-methyl ether (100 mg.) in methanol (27 ml.), there is added 5%hydrochloric acid (3 ml.), and the resultant solution is allowed tostand at room temperature (15 to 30 C.) for 1 hour. The reaction mixtureis condensed to a half volume 'by evaporating methanol at a temperaturelower than '30" C. under reduced pressure. Water is added to thecondensate. The precipitated crystals are collected by filtration andrecrystallized from ethyl acetate to give16}9-ethylthio-17fl-hydroxy-5(10)- estren-B-one (75 mg.) as white platesmelting at 112.5 to 113.5 C. [041 +126.9 (CHCl 133 280,285 my (6: 70).62,321 1728, 1684 cm.-

Analysis.Calcd. for C H O S: C, 71.84; H, 9.04; S, 9.59. Found: C,71.67; H, 8.97; S, 9.52.

Example 2 S 2 SCzHu CHgO To a solution of16/8-ethylthio-1,4-dihydro-3,17fi-estradiol 3-methyl ether (100 mg.) inmethanol (30 ml.), there is added a solution of oxalic acid dihydrate(460 mg.) in water (6 ml.), and the resultant solution is Example 3 To asolution of 165-ethylthio-17fi-hydroxy-5(10)- estren-3-one mg.) inmethanol (16 ml.), there is added 10% hydrochloric acid (4 ml.), and theresultant solution is heated on a steam bath for 10 minutes. Afterevaporation of methanol under reduced pressure, the condensate is shakenwith ether. washed with saturated aqueous sodium bicarbonate and aqueoussodium chloride in order, dried and evaporated. The pale yellowishresidue (78 mg.) is chromatographed on alumina and eluted with a mixtureof petroleum ether and chloroform (6:4). The eluate is crystallized fromether to give l6fi-ethylthio-l7fi-hydroxy-4-estren-3-one (60 mg.) aswhite plates melting at 113 to 114 C. [11],; -8.2. (CHCl f 240 m (6:17,600); 310 312 mu (e: 351

1663, 1618 cmr I Cz s Analysis.Calcd. for C H O S: C, 71.84; H, 9.04; S,9.59. Found: C, 71.88; H, 9.12; S, 9.36.

Example 4 OOOCH:

To a solution of l6fi-ethylthio-L4-dihydro-3,17fl-estradiol 3-methylother mg.) in methanol (12 ml.), there is added 5% hydrochloric acid (8ml.), and the resultant solution is heated on a steam bath for 10minutes. After evaporation of methanol under reduced pressure, thecondensate is shaken with ether. The ether extract is washed withsaturated aqueous sodium bicarbonate and aqueous sodium chloride inorder, dried and evaporated. The pale yellowish residue ischromatographed on alumina and eluted with a mixture of petroleum etherand chloroform (6:4). The eluate is crystallized from ether to give16fl-ethylthio-17B-hydroxy- 4-estren-3-one (90 mg.) as white platesmelting at 113 to 114 C.

A solution of the above-obtainedl6p-ethylthio-l7fihydroxy-4-estren-3-one(90 mg.) in pyridine (1 ml.) andacetic anhydride (1 ml.) is allowed to stand at room temperature (15 to30 C.) overnight. The reaction mixture is condensed under reducedpressure. The residue is crystallized from a mixture of acetone andhexane to give 16p-ethylthio-17,8-hydroxy-4-estren-3-one 17-actate (71mg.) as colorless prisms melting at 152.5 to 153.5 C. [011 +57.5(CHClg),

The ether extract is 5 6 CHSOH CHCI wherein there is a double "bond inone of the positions A 240.5 m (6. 19,000). u 1730, 1668, representedbybmken lines. 1622 cmr 2. 16,6 lower alkylthio-17fi-hydroxy-5(10)-estren-3- Analysis.Calcd. for C H O S: C, 70.17; H,8.57; S, g 5 Found; C, 6995; H S, 5 3.16fl-ethylth1o-17p-hydr0xy-5(l0)-estren-3-one.

w is claimed 4. 16fi-l0wer alkylthio-17fl-hydroxy 4-estren-3-one. 1. Acompound of the formula 5. 16B-ethylthio-17B-hydroxy-4-estren-3-one.

6. 165 ethylt-hio 17 3 hydroxy 4 estren 3-one 17- OH 0 acetate.

lower alkyl References Cited by the Examiner UNITED STATES PATENTS3,170,920 2/1965 Komeno 260-23955 LEWIS GOTTS, Primary Examiner.

1. A COMPOUND OF THE FORMULA